Certain isoxazolylpyridines and isothiazolylpyridines

ABSTRACT

THIS APPLICATION DESCRIBES THE PREPARATION OF ISOXAZOLYLPYRIDINES AND ISOTHIAZOLYLPYRIDINES AS NEW COMPOUNDS AND ALSO THEIR USE IN PREPARING THE CORRESPONDING QUATERNARY ISOXAZOLYLPYRIDINIUM SALTS AND QUATERNARY ISOTHIAZOLYLPYRIDINIUM SALTS. THE QUATERNARY ISOXAZOLYLPYRIDINIUM SALTS AND QUATERNARY ISOTHIAZOLYLPYRIDINIUM SALTS ARE USEFUL FOR THEIR HYPOGLYCEMIC ACTIVITY.

United States Patent Ofice 3,593,829 Patented Aug. 10, 1971 U.S. Cl. 260294.8D 9 Claims ABSTRACT OF THE DISCLOSURE This application describes the preparation of isoxazolylpyridines and isothiazolylpyridines as new compounds and also their use in preparing the corresponding quaternary isoxazolylpyridinium salts and quaternary isothiazolylpyridinium salts. The quaternary isoxazolylpyridinium salts and quaternary isothiazolylpyridinium salts are useful for their hypoglycemic activity.

This application is a continuation-in-part of our application Ser. No. 662,281, filed Aug. 22, 1967, now U.S. Pat. 3,511,848, which in turn is a continuation-in-part of our application Ser. No. 535,714, filed Mar. 21, 1966, now abandoned.

PRIOR ART Applicants are aware of British Pat. 875,887, directed to pyridinium salts. However, the subject matter of the present application is not disclosed therein.

SUMMARY OF THE INVENTION This invention relates to new organic compounds. More particularly, it relates to isoxazolylpyridines and isothiazolylpyridines, intermediates for preparation of quaternary isoxazolylpyridinium salts and quaternary isothiazolylpyridim'um salts.

The new compounds of the present invention may be illustrated by the following formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, and trihalo(lower)alkyl, R is selected from the group consisting of hydrogen and lower alkyl,

Z is a trivalent radical selected from the group consisting of f :N =N O and and the dotted line represents one double bond, the position of which is dependent upon the definition of Z. When Z is the double bond is adjacent to R and when Z has the other meanings, the double bond is adjacent to the pyridinium ring.

The term lower alkyl is intended to include those having 1 to 4 carbon atoms. The term halo is intended to include chlorine, bromine, iodine and fluorine.

In general, the compounds are crystalline solids, soluble in water.

The compounds of the present invention may be prepared by either of several general reaction sequences. Thus, a l-(4-pyridyl)l,3-alkyldione or a l-(4-pyridyl)- 1,3-alkyldione salt is reacted with a hydroxylamine salt such as the hydrochloride, in a polar solvent, such as water or alcohol, at a temperature of 25 to C. for a time of one minute to twenty-four hours with or without the addition of a base, such as sodium carbonate, to provide either a 4-isoxazolylpyridine or a l-(4-pyridyl)- 1,3-alkyldione oxime. When an oxime is formed, it is converted to a 4-isoxazolylpyridine by treatment with a dehydrating agent, such as acetyl chloride or concentrated sulfuric acid, at a temperature of 0 to 100 C. for a time of one minute to twenty-four hours. Alternatively, an acetylene is allowed to react with a pyridine nitrile oxide, formed in situ from an isonicotinohydroxarnyl chloride and triethylamine, to provide a 4-isoxazolylpyridine. For the synthesis of isothiazolylpyridinium salts, and isoxazolylpyridine is hydrogenated to provide an amino-pyridyl-butenone, which is fused with phosphorus pentasulfide to provide an isothiazolylpyridine.

These reactions are illustrated as follows:

Method D wherein R and R are as hereinbefore defined.

The 4 isoxazolylpyridines and 4-isothiazolylpyridines are quaternized to 4-isoxazolylpyridinium salts and 4- isothiazolylpyridinium salts by reaction with a lower alkyl, lower alkenyl, cycloalkyl(lower)alkyl, or lower alkoxy (lower)alkyl halide at a temperature of '0 to l50 C. with or without a solvent, such as alcohol, for a time of one minute to twenty-four hours in an open vessel or a sealed 'bomb.

Among the compounds of the present invention, are, for example; 4-(3-methyl isoxazolyl)pyridine, 4-(3- ethyl 5 isoxazolyl)pyridine, 4 (3 cyclopropyl-S- isoxazolyl)pyridine, 4 (3 trifluoromethyl-S-isoxazolyl) pyridine, 4 (5 trifluoromethyl 3 isoxazolyl)pyridine, 4 (5 isoxazolyl)pyridine, 4 (5 methyl-3-isoxazolyl) pyridine, 3 methyl 4 (3 methyl 5 isoxazolyl)pyridine, 4 (5 methyl 3 isothiazolyl)pyridine and 4-(3- methyl-S-isothiazolyl)pyridine.

The compounds directl prepared from the intermediates of the present invention show hypoglycemic activity based on the following data which shows a reduction in blood sugar levels in mice, guinea pigs and cockerels. When the compounds are administered orally to normal mice, a reduction of blood sugar levels is observed. Mice used in these studies are MF-1 (Manor Farms, 18-25 grams). The compounds are administered by gavage as saline solutions. Control animals receive an equivalent volume of vehicle. Food is withheld from animals after dosing. Blood glucose is determined 2 to 6 hours after dosing by the method of Hellman [J. Biol. Chem., 120, 51 (1937)] as adapted to the Technicon AutoAnalyzer and is expressed as percent change from saline controls. Blood samples are obtained from the tail veins of mice. The testing data is summarized in Table I.

YL-5ISOXAZOLYL)PYRIDINIUM OHLO RIDE IN COCKER- ELS, GUINEA PIGS AND ALLOXANIZED MICE Time Percent Dose, after reduction 2 mmolldosing, in blood Species and treatment kg. hrs. glucose Cockercls. drug (10) 1.99 2 3 43 47 Guinea pigs, saline (10), drug (6) 1. 6 13 2 3 54= 6 Alloxanized mice, saline (28), drug (27)- 0.6 4 11= =2 3 47= =5 l Cockerels and guinea pigs were lasted 24 hours before dosing Food was withheld from all animals after dosings.

2 Values are means t SE. of number of animals indicated in parentheses and are expressed as percent reduction from predose levels or from saline control in the case of cockerels (blood glucose of 10 saline control cockerels was 143*5 mg. percent).

3 Significantly different from control.

These results show that the compounds prepared from the intermediates of the present invention are useful in the lowering of blood glucose in normal and hyperglycemic Warm-blooded animals.

The compounds prepared from the intermediates of this invention can be used in compositions such as tablets; the principal active ingredient is mixed with conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, and fractionally similar materials as pharmaceutical diluents or carriers. The tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form alfording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed TABLE I.DECREASE IN BLOOD GLUCOSE IN NORMAL MICE AFTER ORAL ADMINIS- TRATION OF ISOXAZOLYLPYRIDINIUM SALTS Compound Percent decrease in blood glucose, dose,

l-methyli-(3-methyl-5-isoxazolyl)pyridinium chloride. 1-methyl4-(3-ethyl-5-isoxazolyl)pyridinium chloride 1-allyl-4-(3-methyl-5-isoxazolyl)pyridinium chloride 1-methyl-4-(5-isoxazolyl)pyridinium chloride.

1,3-dimetliyl-4-(3-methyl-5-isoxazolyl)pyridinium chloride 1-(2-1netl1oxyethyl)-4-(3 metl1yl-5-isoxazolyl) pyridinium chloride l-methyl-443-methyl-5-isoxazolyl)pyridinium iodide l-methyl-i-(5-methyl-3-isoxazolyl)-pyridinium iodide.

X Values are means i standard errors of 4 to 8 mice per dose and are expressed as percent decrease from predose values.

2 159 mg./kg. 3 318 Ing./kg. 4 477 mg./kg. 5 mgJkg.

in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and acetyl alcohol, cellulose acetate and the like. A particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating.

The liquid forms in which the isoxazolylpyridinium salts and isothiazolylpyridinium salts may be incorporated for administration include suitably flavored emulsions with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Sterile suspensions or solutions are required for parenteral use. Isotonic preparations containing suitable preservatives are also highly desirable for injection use.

Examples of suitable oral dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfulls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing and other forms as herein described.

DETAILED DESCRIPTION The preparation of the compounds of this invention and their conversion into the isoxazolylpyridinium salts and isothiazolylpyridinium salts are described in greater detail in conjunction with the following examples.

EXAMPLE I Preparation of 4-(3-methyl-5-isoxazolyl) pyridine A solution of 22 g. (0.13 mole) of 4-acetoacetylpyridine, 14 g. of hydroxylamine hydrochloride, 14 g. of sodium carbonate, 150 ml. of water, and 100 ml. of ethanol is heated under reflux for 12 hours. Then, 100 ml. of solvent is allowed to distill from the mixture, which is then extracted with benzene. The benzene solution is concentrated under reduced pressure to a colorless solid. Recrystallization from cyclohexane provides 14 g. (66%) of colorless crystals, melting point 62-65 C.

mati. 263

EXAMPLE H Preparation of 4-(3-ethy1-5-isoxazoly1)pyridine A mixture of 40.5 g. (0.23 mole) of 1-(4pyridyl)-l,3- pentanedione, 17.4 g. of hydroxylamine hydrochloride, 24.4 g. of sodium carbonate, 200 ml. of water, and 100 ml. of ethanol is heated under reflux for 18 hours. Then, 100 ml. of solvent is distilled, and the mixture is extracted with benzene. Concentration of the benzene solution leaves a red liquid which is crystallized from hexane to provide colorless crystals, melting point 48-49" C.

EXAMPLE III Preparation of 4-(5-isoxazoly1)pyridine To a solution of 103 g. (0.6 mole) of 1-(4-pyridy1)- 1,3-propanedione sodium salt in 500 ml. of water is added 44 g. of hydroxylamine hydrochloride. After several minute, the solution is adjusted to pH 8 With sodium carbonate, and the solid which separates is collected. Recrystallization from methanol gives 52 g. of colorless crystals, melting point 152-153 C. dec., of 1-(4-pyridyl)-1,3-propanedione 3-oxime.

A mixture of 38 g. (0.22 mole) of 1-(4-pyridyl)-1,3- propanedione 3-oxime and 150 ml. of acetyl chloride is heated under reflux for 2 hours. The excess acetyl chloride is distilled, and the residue is taken up in water and made basic with sodium hydroxide. The mixture is extracted with ether. Concentration of the ether solution leaves a yellow solid, which is recrystallized from ether to give 11 g. of colorless crystals, melting point 101- 102 C.

EXAMPLE IV Preparation of 4-(5-trifluoromethyl-3-isoxazolyl)pyridine A solution of 2.2 g. (0.01 mole) of 1-(4 pyridyl)-4,4,4- trifluoro-l,3-butanedione, 0.7 g. of hydroxylamine hydrochloride, 20 ml. of ethanol, 5 ml. of Water and 0.7 g. of sodium carbonate is heated under reflux for 12 hours, concentrated to a volume of 5 ml., and diluted with water. The solid which separates is recrystallized from isopropyl alcohol-water to provide 1.85 g. of colorless prisms, melting point 187 C., of 1-(4-pyridyl)-4,4,4-trifluoro-1,3-butane-dione l-oxime.

To 25 ml. of concentrated sulfuric acid is added during 15 minutes with stirring 10.0 g. of 1- (4-pyridyl)-4,4,4- trifluoromethyl-1,3-butanedione l-oxime. The solution is poured into ice water and made basic with 10 N sodium hydroxide. The solid which separates is collected and recrystallized from ethanol-water to provide colorless prisms, melting point 82-83 C.

EXAMPLE V Preparation of 3-methyl-4-(3-methyl-5-isoxazolyl) pyridine 0113011 maX.

EXAMPLE VI Preparation of 4-(5-methyl-3-isoxazolyl)pyridine To a cold (40 C.) solution of 75 ml. of methylacetylene, 400 ml. of ether and 19.3 g. (0.10 mole) of isonicotinoylhydroxamyl chloride hydrochloride is added dropwise during 2 hours, a solution of 28 ml. of triethylamine in ml. of ether. The mixture is stirred at 40 C. for 5 hours, allowed to stand at room temperature for 20 hours and diluted with water and sufficient 1 N sodium hydroxide to make the mixture alkaline. The mixture is extracted with ether and chloroform, and the organic solution is dried over anhydrous magnesium sulfate and sublimation at 100 C. (15 min.) gives colorless needles, melting point 8687 C.

EXAMPLE VII Preparation of 3-amino-1- (4-pyridyl) -2-buten-1-0ne A mixture of 20 g. (0.125 mole) of 4-(3-methyl-5-isoxazolyl)pyridine, 2.5 g. of platinum oxide, and 300 ml. of ethanol is hydrogenated at 40 p.s.i. for 3 hours. The mixture is filtered, and the filtrate is concentrated to a solid. Recrystallization from ethyl acetate provides colorless crystals, melting point 2112l3 C.

EXAMPLE VHI Preparation of 4-(3-methyl-5-isothiazolyl)pyridine A mixture of 3.6 g. (0.022 mole) of 3-amino-1-(4-pyridyl)-2-buten-1-one and 6 g. of phosphorus pentasulfide is fused at C. for 1 hour, cooled to room temperature, warmed with 1 N potassium hydroxide, and extracted with chloroform. The chloroform extract is dried over anhydrous magnesium sulfate and concentrated to a solid. Sublimation at 90 (18 min.) provides colorless needles, melting point 56-60 C.

EXAMPLE 1x Preparation of l-aminol-(4-pyridyl)- l-buten-3-one A mixture of 0.48 g. (0.003 mole) of 4-(5-methyl-3- isoxazolyl)pyridine, 0.1 g. of platinum oxide, and 35 ml. of ethanol is hydrogenated at 1 atmosphere for 18 hours and filtered. The filtrate is concentrated to a solid. Recrystallization from ethyl acetate-hexane followed by sublimation at 155 (13 mm.) provides pale yellow crystals, melting point 152-l53 C.

EXAMPLE X Preparation of 4- -methyl-3-isothiazolyl pyridine A mixture of 1.0 g. (0.0062 mole) of l-amino-1-(4- pyridyl)-1-buten-3-one and 1.8 g. of phosphorus pentasulfide is fused at 190 C. for /2 hour, cooled. diluted with water, made alkaline with 1 N potassium hydroxide, 'and extracted with chloroform. The chloroform solution is dried over anhydrous magnesium sulfate and concentrated to a solid. Sublimation at 115 C./(l5 mm.) provides colorless needles, melting point 4952 C.

EXAMPLE XI Preparation of 1-methyl-4-(3-methyl-5-isoxazolyl) pyridinium chloride A mixture of 100 g. (0.62 mole) of 4-(3-methyl-5-isoxazolyl)pyridine and 350 ml. of methyl chloride is heated at 100 C. in a bomb for 15 hours. The excess methyl chloride is allowed to evaporate, and the residue is recrystallized from isopropyl alcohol to afford 56 g. (43%) of colorless crystals, melting point 248 C., dec.

EXAMPLE XII Preparation of 1-methyl-4-(3-ethyl-5-isoxazolyl) pyridinium chloride A mixture of 8.7 g. (0.05 mole)of 4-(3-ethyl-5-isoxazolyl)pyridine and ml. of methyl chloride is heated at 95 C. in a bomb for 17 hours. The excess methyl chloride is allowed to evaporate, and the residue is recrystallized from isopropyl alcohol to give colorless crystals, melting point ZOO-201 C., dec.

EXAMPLE XIII EXAMPLE XIV Preparation of l-n-propyl-4- 3-methyl-5-isoxazolyl) pyridinium bromide A mixture of 3.2 g. (0.02 mole) of 4-(3-methyl-5- isoxazolyl)pyridine and 10 ml. of n-propyl bromide is heated in a bomb at 100 C. for 20 hours. The solid which forms is collected. washed with ether, and recrystallized from isopropyl alcohol to provide colorless crystals, melting point 180-182" C.

EXAMPLE XV Preparation of 1-ethyl-4-(3-methyl-5-isoxazolyl) pyridinium iodide A solution of 3.20 g. (0.02 mole) of 4-(3-methyl-5- isoxazolyl)pyridine, 4.5 g. of ethyl iodide, and 25 ml.

8 of ethanol is heated under reflux for 2 hours, and then concentrated to dryness. The residue is crystallized from isopropyl alcohol to provide yellow crystals, melting point l93l94 C., dec.

EXAMPLE XVI Preparation of 1-cyclopropylmethyl-4-(3-methyl-5- :isoxazolyl)pyridinium bromide A solution of 3.20 g. (0.02 mole) of 4-(3-methyl-5- isoxazolyl)pyridine and 10 ml. of cyclopropylmethyl bromide is heated on a steam bath for /2 hour. Two layers form, and the lower layer is separated and recrystallized from acetonitrile to provide colorless crystals, melting point ll66 C., dec.

EXAMPLE XVII Preparation of l-(2-methoxyethyl)-4-(3-methyl-5- isoxazolyl) pyridinium chloride A mixture of 3.2 g. (0.02 mole) of 4-(3-methyl-5- isoxazolyl)pyridine and 2 g. of 2-methoxyethyl chloride is heated on a steam bath for 19 hours. The mixture is treated With ether and the insoluble tarry residue is stirred with acetone to provide 2.4 g. of tan solid, melting point 7277 C. Recrystallization from isopropyl alcohol provides off-white crystals, melting point 73-64" C.

EXAMPLE XVIII Preparation of 1-methyl-4- 5 -isoxazolyl pyridinium chloride A mixture of 2.5 g. (0.017 mole) of 4-(5-isoxazolyl) pyridine and 20 ml. of methyl chloride is heated at C. in a bomb for 20 hours. The excess methyl chloride is allowed to evaporate and the solid residue is recrystallized from acetonitrile to provide 2.2 g. (65%) of colorless crystals, melting point 182l83 C., dec.

EXAMPLE XIX Preparation of 1-methyl-4-(5-isoxazolyl)pyridinium iodide A solution of 0.5 g. (0.003 mole) of 4-(5-isoxazolyl) pyridine, 3 ml. of methyl iodide, and 20 ml. of methanol is heated under reflux for 20 hours. The solvent is removed under reduced pressure and the residue is recrystallized from methanol to provide tan crystals, melting point 212-213 C., dec.

EXAMPLE XX Preparation of 1-ethyl-4-(3-ethyl-5-isoxazolyl) pyridinium iodide A solution of 3.5 g. (0.02 mole) of 4-(3-ethyl-5- isoxazolyl)pyridine, 4.5 g. of ethyl iodide, and 25 ml. of ethanol is heated under reflux for 2 hours, and then concentrated to an oil. Crystallization from isopropyl alcohol provides yellow crystals, melting point 154 C., dec.

EXAMPLE XXI Preparation of 1-1nethyl-4-( 5 -trifluoromethyl-3- isoxazolyl)pyridinium chloride A mixture of 1.5 g. (0.007 mole) of 4-(5-trifluoromethyl-3-isoxazolyl)pyridine and 5 ml. of methyl chloride is heated in a bomb at C. for 4 hours. The excess methyl chloride is allowed to evaporate, and the solid residue is recrystallized from isopropyl alcohol to provide colorless crystals, melting point 230, dec.

9 EXAMPLE XXII Preparation of 1,3 -dimethyl-4- S-methyl-S-isoxazolyl) pyridinium chloride A mixture of 1.9 g. (0.011 mole) of 3-methy1-4-(3- methyl-S-isoxazolyl)pyridine and 20 ml. of methyl chloride is heated in a bomb at 90 C. for 18 hours. The excess methyl chloride is allowed to evaporate, and the solid residue is recrystallized from acetonitrile to provide colorless crystals, melting point 246-247 C., dec.

EXAMPLE XXIII Preparation of 1-n-propyl-4-(3-ethyl-5-isoxazo1yl) pyridinium bromide A solution of 3.5 g. (0.02 mole) of 4-(3-ethyl-5- isoxazolyl)pyridine and ml. of n-propyl bromide is heated at 100 C. in a bomb for 18 hours. The excess n-propyl bromide is decanted from a tar which forms, and the latter is triturated with acetone to provide colorless crystals. Recrystallization from isopropyl alcoholether gives colorless needles, melting point 153 C.

EXAMPLE XXIV Preparation of 1-methyl-4-(3-methyl-5-isothiazolyl) pyridinium iodide A solution of 0.4 g. (0.0023 mole) of 4-(3-methyl-5- isothiazolyl)pyridine, 2 ml. of methyl iodide, and m1. of ethanol is heated under reflux for 1.5 hours, cooled, and diluted with ether. A solid separates and is recrystallized from acetonitrile-ether to provide yellow crystals, melting point 176-177 C., dec.

EXAMPLE XXV Preparation of 1-methyl-4-(5-methyl-3-isothiazolyl) pyridinium iodide A solution of 0.26 g. (0.0015 mole) of 4-(5-methyl-3- isothiazolyl)pyridine, 2 ml. of methyl iodide, and 100 n11. of ethanol is heated under reflux for 1.5 hours, cooled, and diluted with ether. A solid separates and is recrystallized from ethanol-ether to provide yellow crystals, melting point 110112 C.,- dec.

10 We claim: 1. An isoxazolylpyridine or isothiazolylpyridine compound of the formulae:

and

wherein Ris selected from the group consisting of hydrogen, lower alkyl and trifiuoromethyl; R is selected from the group consisting of hydrogen and lower alkyl and X is oxygen or sulfur.

2. The isoxazolylpyridine according to claim 1: 4-(3- methyl-S-isoxazolyl pyridine.

3. The isoxazolylpyridine according to claim 1: 4-(3- ethyl-S-isoxazolyl)pyridine.

4. The isoxazolylpyridine according to claim 1: 4-(5- isoxazolyl)pyridine.

5. The isoxazolylpyridine according to claim 1: 4-(5- trifluoromethyl-3 -isoxazolyl) pyridine.

6. The isoxazolylpyridine according to claim 1: 3- methyl-4- 3-methyl-5-isoxazolyl) pyridine.

7. The isoxazolylpyridine according to claim 1: 4-(5- methyl-3 -isoxazolyl) pyridine.

8. The isothiazolylpyridine according to claim 1: 4-(5- methyl-3-isothiazolyl)pyridine.

9. The isothiazolylpyridine according to claim 1: 4-(3- methyl-S-isothiazolyl) pyridine.

References Cited UNITED STATES PATENTS 3,277,105 10/1966 Schmidt et al. 260-296R HENIRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US. Cl. X.|R.

260269R, 297R, 296M, 294.9; 424263 

